The present study was undertaken to assess the role of p53 in the neurotoxic effects of methamphetamine on the nigrastriatal dopamine system of mice. P53 has been known to be involved in kainic-induced apoptosis in the hippocampus and in radiation-induced apoptosis in vitro, and in anoxic injury after vascular occlusion. We thus wanted to know if METH-induced neurotoxicity was mediated, in part, by expression of p53. We have used p53 knock-out mice toa ssess the participation of p53 in the loss of dopaminergic terminals observed after administration of methamphetamine (METH). Towards that end, wild-type mice as well as heterozygous and homozygous p53 knock-out male mice were injected with toxic dosages of METH. METH cause a marked dose-dependent loss of dopamine uptake sites in both the striatum and the nucleus accumbens of wild-type mice. However, this METH-induced loss was attenuated in both homozygous and heterozygous p53 knock-out mice. Moreover, METH caused marked increased in p53-like immunoreactivity in the striata of wild-type mice, but very little change in heterozygous p53 knowck-out mice. No p53 immunostaining was detected in the homozygous p53 knock-out mice. These resuts provide the first evidence for a role of p53 in the deleterious effects of a drug acting on dopaminergic systems.